α-Synuclein synaptic pathology and its implications in the development of novel therapeutic approaches to cure Parkinson's disease

Abstract

Parkinson's disease (PD) is characterized by a progressive loss of dopamine (DA) neurons of the nigrostriatal system and by the presence of Lewy bodies (LB), proteinaceous inclusions mainly composed of filamentous α-synuclein aggregates. Alpha-synuclein is a natively unfolded protein which plays a central role in the control of dopaminergic neuronal functions and which is thought to be critically implicated in PD pathophysiology. Indeed, besides the fact that α-synuclein is the main protein component of LB, genetic studies showed that mutations and multiplications of the α-synuclein gene are responsible for the onset of familial forms of PD. A large body of evidence indicates that α-synuclein pathology at dopaminergic synapses may underlie the onset of neuronal cell dysfunction and degeneration in the PD brain. Thus, since the available therapeutic approaches to cure this disease are still limited, we hypothesized that the analysis of the α-synuclein synaptic proteome/lipidome may represent a tool to identify novel potential therapeutic targets to cure this disorder. We thus performed a critical review of studies describing α-synuclein pathophysiology at synaptic sites in experimental models of PD and in this paper we outline the most relevant findings regarding the specific modulatory effects exerted by α-synuclein in the control of synaptic functions in physiological and pathological conditions. The conclusions of these studies allow to single out novel potential therapeutic targets among the α-synuclein synaptic partners. These targets may be considered for the development of new pharmacological and gene-based strategies to cure PD.